Development of cebranopadol, a potent dual MOP/NOP agonist, for the treatment of Opioid Use Disorder (OUD)

开发cebranopadol，一种有效的双重MOP/NOP激动剂，用于治疗阿片类药物使用障碍（OUD）

• 批准号: 10759100
• 负责人: Mark K Greenwald
• 金额: $ 332.96万
• 依托单位: PARK THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759100
• 关键词: Acute; Address; Affect; Affinity; Agonist; Apnea; Behavior; Binding; Breathing; Buprenorphine; Clinical; Clinical Data; Clinical Research; Confidence Intervals; Crossover Design; Data; Development; Dosage Forms; Dose; Double-Blind Method; Drug Metabolic Detoxication; Evaluation; Fentanyl; Future; Heroin; Hour; Human; Hydromorphone; Incidence; Intravenous; Maintenance; Measures; Mediating; Methadone; Morphine; Motor; Naltrexone; ORL1 receptor; Opiate Addiction; Opioid; Opioid Peptide; Opioid Receptor; Oral; Oral Administration; Outcome Measure; Overdose; Oxycodone; Oxygen; Pain; Participant; Patients; Peptide Receptor; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physical Dependence; Placebos; Precipitation; Randomized; Rattus; Receptor Activation; Recreation; Regimen; Respiratory physiology; Risk; Safety; Schedule; Self Administration; Signs and Symptoms; Solid; Testing; Therapeutic; Tramadol; Treatment Efficacy; Ventilatory Depression; Visual; Withdrawal; Withdrawal Symptom; abuse liability; addiction; alternative treatment; analog; antagonist; attenuation; cocaine self-administration; craving; effective therapy; efficacy evaluation; efficacy study; experience; fentanyl self-administration; improved; intravenous administration; meetings; morphine administration; mortality; nociceptin; opiate tolerance; opioid epidemic; opioid injection; opioid misuse; opioid overdose; opioid use; opioid use disorder; opioid user; opioid withdrawal; overdose death; overdose risk; preclinical safety; preclinical study; primary outcome; programs; receptor; safety study; synthetic drug; verbal

ABSTRACT/SUMMARY The U.S. is experiencing a crisis of opioid misuse, addiction, and overdose; in the most recent year, there were over 100,000 drug-related overdose deaths, 75% of which involved opioids. Current pharmacotherapies for opioid use disorder (OUD) target mu opioid peptide (MOP) receptors, one of five classes of opioid receptors. These therapies include the full MOP agonist methadone, the partial MOP agonist buprenorphine, and the MOP antagonist naltrexone. There are several drawbacks in using these medications to treat OUD, which include the potential for abuse, development of physical dependence, and risk of overdose, particularly for methadone and buprenorphine. Buprenorphine and naltrexone also trigger severe withdrawal symptoms. There is thus an urgent need for an improved therapeutic for the treatment of OUD. Cebranopadol (TRN-228) is a first-in-class synthetic drug developed for its dual-action mechanism in treating pain, mediated by high affinity and potency for both MOP and nociceptin/orphanin FQ receptor (NOP). NOP receptor activation has been associated with reduced development of tolerance, abuse-related behavior, addiction, and physical dependence. In this UG3/UH3 proposal, Park Therapeutics is developing TRN-228 as a first-in-class dual MOP/NOP agonist that can be used as a safe and effective treatment for OUD. Preliminary nonclinical and clinical data indicate that cebranopadol has low potential for abuse and physical dependence and produces milder respiratory depression compared to pure MOP agonists such as morphine and oxycodone. TRN-228 also decreases morphine, heroin, and cocaine self-administration in rats and did not induce withdrawal when given to opioid-dependent rats. The UG3 phase of this proposal will test whether oral TRN-228 is a safe and potentially effective alternative treatment for OUD, based on the following Specific Aims: 1) determining the effects of TRN-228 on intravenous fentanyl self-administration and fentanyl-induced respiratory depression in opioid-dependent rats, 2) determining the IV abuse potential of TRN-228, and 3) assessing the ability of TRN-228 to suppress withdrawal. Upon meeting the UG3 Go/No-Go milestones, Park will progress to the UH3 phase which will demonstrate the therapeutic efficacy of TRN-228 in decreasing opioid use with low risk of withdrawal or abuse, which will be accomplished by 4) determining the effects of TRN-228 on fentanyl-induced respiratory depression in opioid-tolerant participants and 5) evaluating the ability of TRN-228 to block the subjective effects of hydromorphone. These studies will significantly advance the field by establishing the safety and preliminary efficacy of TRN-228. Successful completion of these aims will guide future efforts to establish a clinical program for FDA approval.

抽象/总结